MIPS-UC San Diego team identify promising protein targets to combat heart disease
06 September 2016
Using a unique computational approach to rapidly sample, in millisecond time intervals, proteins in their natural state as they gyrate, bob and weave, a research team from Monash University and UC San Diego has identified promising candidates that may selectively combat heart disease, from arrhythmias to cardiac failure.
Reported in Proceedings of the National Academy of Sciences (PNAS), the research used supercomputers to perform an unprecedented survey of protein structures, using a technique called “accelerated molecular dynamics” or aMD – a method that performs a more complete sampling of the myriad shapes and conformations that a target protein molecule may go through.
Though highly effective in most cases, today’s heart medications – many of which act on M2 muscarinic acetylcholine receptors or M2 mChRs, decreasing heart rate and reducing heart contraction -- may carry side effects, sometimes serious. That’s because the genetic sequence of M2 mChR’s primary ‘orthosteric’ binding site is “highly conserved,” and found in at least four other receptor types that are widely spread in the body, yielding unwanted results.
For this reason, drug designers are seeking a different approach, homing in on different types of molecular targets, so-called “allosteric binding sites”, which reside away from the receptor’s primary binding site and are built around a more diverse genetic sequence and structure than their counterpart “orthosteric” binding sites. Essentially, allosteric modulators act as a kind of cellular dimmer-switch that, once turned on, ‘fine tunes’ the activation and pharmacological profile of the target receptor.
In particular, drug designers have begun to aggressively search for allosteric modulators to fine-tune medications that bind to G protein-coupled receptors (GPCRs), the largest and most diverse group of membrane receptors in animals, plants, fungi and protozoa. These cell surface receptors act like an inbox for messages in the form of light energy, hormones and neurotransmitters, and perform an incredible array of functions in the human body. In fact, between one-third to one-half of all marketed drugs act by binding to GPCRs, treating diseases including cancer, asthma, schizophrenia, Alzheimer’s and Parkinson’s disease, and heart disease.
Though many of the GPCR drugs have made their way to the medicine cabinet, most -- including M2 mChR targeted drugs -- exhibit side effects owing to their lack of specificity. All these drugs target the orthosteric binding sites of receptors, thus creating the push to find more targeted therapies based on allosteric sites. However molecules that bind to these allosteric sites have proven extremely difficult to identify using conventional high-throughput screening techniques.
In the newly published study, 38 lead compounds were selected from a large database of compounds from the National Cancer Institute in the US.
A team of MIPS researchers, including Professors Arthur Christopoulos and Patrick Sexton, PhD candidate, Ee Von Moo, and co-lead investigator, Dr. Celine Valant, then collaborated with the UCSD team, led by Dr. Yinglong Miao and Prof. J. Andrew McCammon, to use cutting cutting edge, computationally enhanced simulations to account for binding strength and receptor flexibility. About half of these compounds exhibited the hallmarks of allosteric behavior in subsequent in vitro experiments, with about a dozen showing affinity to the M2 mChR binding site. Of these, the researchers highlighted two showing both affinity and high selectivity in studies of cellular behavior.
“To our knowledge, this study demonstrates for the first time an unprecedented successful structure-based approach to identify chemically diverse and selective GPCR allosteric modulators with outstanding potential for further structure-activity relationship studies,” they wrote.
The next steps will involve an investigation of the chemical properties of these novel molecules by the Monash team.
“This is just the beginning. We believe that it will be possible to apply our combined cutting-edge in silico and in vitro techniques to a wide array of receptor targets that are involved in some of the most devastating diseases” said Dr. Valant and Prof. Christopoulos.
Also participating in the study was Dahlia Goldfeld, from the UC San Diego Department of Pharmacology.